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Dissecting the prevention of estrogen-dependent breast carcinogenesis through Nrf2-dependent and independent mechanisms

Authors Giudice A, Barbieri A, Bimonte S, Cascella M, Cuomo A, Crispo A, D'Arena G, Galdiero M, Della Pepa ME, Botti G, Caraglia M, Capunzo M, Arra C, Montella M

Received 8 August 2018

Accepted for publication 14 December 2018

Published 24 June 2019 Volume 2019:12 Pages 4937—4953

DOI https://doi.org/10.2147/OTT.S183192

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 3

Editor who approved publication: Dr Tohru Yamada


Aldo Giudice,1 Antonio Barbieri,2 Sabrina Bimonte,3 Marco Cascella,3 Arturo Cuomo,3 Anna Crispo,1 Giovanni D’Arena,4 Massimiliano Galdiero,5 Maria Elena Della Pepa,5 Gerardo Botti,6 Michele Caraglia,7 Mario Capunzo,8 Claudio Arra,2 Maurizio Montella1

1Epidemiology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy; 2S.S.D Sperimentazione Animale, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy; 3Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy; 4Hematology and Stem Cell Transplantation Unit, IRCCS Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy; 5Department of Experimental Medicine, Università della Campania “Luigi Vanvitelli”, 80134 Naples, Italy; 6Scientific Direction, Istituto Nazionale Tumori-IRCCS “Fondazione G. Pascale”, Naples, Italy; 7Department of Biochemistry, Biophysics and General Pathology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; 8Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy

Abstract: Breast cancer is the most common malignancy among women worldwide. Various studies indicate that prolonged exposure to elevated levels of estrogens is associated with development of breast cancer. Both estrogen receptor-dependent and independent mechanisms can contribute to the carcinogenic effects of estrogens. Among them, the oxidative metabolism of estrogens plays a key role in the initiation of estradiol-induced breast cancer by generation of reactive estrogen quinones as well as the associated formation of oxygen free radicals. These genotoxic metabolites can react with DNA to form unstable DNA adducts which generate mutations leading to the initiation of breast cancer. A variety of endogenous and exogenous factors can alter estrogen homeostasis and generate genotoxic metabolites. The use of specific phytochemicals and dietary supplements can inhibit the risk of breast cancer not only by the modulation of several estrogen-activating enzymes (CYP19, CYP1B1) but also through the induction of various cytoprotective enzymes (eg, SOD3, NQO1, glutathione S-transferases, OGG-1, catechol-O-methyltransferases, CYP1B1A, etc.) that reestablish the homeostatic balance of estrogen metabolism via nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent and independent mechanisms.

Keywords: reactive estrogen quinones, breast carcinogenesis, depurinating estrogen–DNA adducts, dietary phytochemicals, nuclear factor erythroid 2-related factor 2

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